HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging
S. Michal Jazwinski
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorSangkyu Kim
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Contributed equally.
Search for more papers by this authorJianliang Dai
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Genetics Department, University of Georgia, Athens, GA 30602, USA
Contributed equally.
Search for more papers by this authorLi Li
Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorXiuhua Bi
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorJames C. Jiang
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorJonathan Arnold
Genetics Department, University of Georgia, Athens, GA 30602, USA
Search for more papers by this authorMark A. Batzer
Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
Search for more papers by this authorJerilyn A. Walker
Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
Search for more papers by this authorDavid A. Welsh
Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorChristina M. Lefante
School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorJulia Volaufova
School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorLeann Myers
Department of Biostatistics, School of Public Health and Tropical Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorL. Joseph Su
School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Present address: Modifiable Risk Factors Branch, National Cancer Institute, Rockville, MD 20892, USA.
Search for more papers by this authorDorothy B. Hausman
Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA
Search for more papers by this authorMichael V. Miceli
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorEric Ravussin
Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
Search for more papers by this authorLeonard W. Poon
Institute of Gerontology, University of Georgia, Athens, GA 30602, USA
Search for more papers by this authorKatie E. Cherry
Department of Psychology, Louisiana State University, Baton Rouge, LA 70803, USA
Search for more papers by this authorMichael A. Welsch
Department of Kinesiology, Louisiana State University, Baton Rouge, LA 70803, USA
Search for more papers by this authorfor the Georgia Centenarian Study and the Louisiana Healthy Aging Study
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorS. Michal Jazwinski
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorSangkyu Kim
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Contributed equally.
Search for more papers by this authorJianliang Dai
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Genetics Department, University of Georgia, Athens, GA 30602, USA
Contributed equally.
Search for more papers by this authorLi Li
Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorXiuhua Bi
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorJames C. Jiang
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorJonathan Arnold
Genetics Department, University of Georgia, Athens, GA 30602, USA
Search for more papers by this authorMark A. Batzer
Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
Search for more papers by this authorJerilyn A. Walker
Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
Search for more papers by this authorDavid A. Welsh
Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorChristina M. Lefante
School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorJulia Volaufova
School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorLeann Myers
Department of Biostatistics, School of Public Health and Tropical Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorL. Joseph Su
School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Present address: Modifiable Risk Factors Branch, National Cancer Institute, Rockville, MD 20892, USA.
Search for more papers by this authorDorothy B. Hausman
Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA
Search for more papers by this authorMichael V. Miceli
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorEric Ravussin
Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
Search for more papers by this authorLeonard W. Poon
Institute of Gerontology, University of Georgia, Athens, GA 30602, USA
Search for more papers by this authorKatie E. Cherry
Department of Psychology, Louisiana State University, Baton Rouge, LA 70803, USA
Search for more papers by this authorMichael A. Welsch
Department of Kinesiology, Louisiana State University, Baton Rouge, LA 70803, USA
Search for more papers by this authorfor the Georgia Centenarian Study and the Louisiana Healthy Aging Study
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Search for more papers by this authorSummary
The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were recruited and stratified according to their genetically inferred ethnic affiliation to account for population structure. Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These results were replicated in a second population. A profile of healthy aging was developed using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity.
Supporting Information
Fig. S1 Haplotype blocks in APOE, HRAS1, and LASS1. Haplotype blocks for the three genes were examined using Haploview after stratifying the populations using Structure assignment probabilities of 0.8 and 0.9 (in parentheses below) for European origin. A – Georgia (0.9), B – Georgia (0.8), C – Louisiana (0.9), and D – Louisiana (0.8). Among the differences between the two populations, the large haplotype block in HRAS1 that is evident in the Louisiana population at 0.9 and 0.8 assignment probabilities is only apparent in Georgia at 0.9 assignment probability, and the haplotype block seen in LASS1 in the Louisiana population is not apparent in the Georgia population. No tag SNP in the haplotype blocks were identified.
Table S1 APOE association with exceptional longevity
Table S2 APOE association with exceptional longevity in the major population strata
Table S3 Lack of association with exceptional longevity of variants in HRAS1 and LASS1 in the major population strata
Table S4 Association of combinations of haplotypes in APOE, HRAS1, and LASS1 with exceptional longevity
Table S5 Association of additional haplotypes in individual genes and in combinations of two genes with exceptional longevity
Table S6 List of deficits in deficit accumulation index
Table S7 Age and gender composition of the study samples
Table S8 Genotyped loci
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